tbuckley/cabot-search huggingface dataset:
Neoadjuvant durvalumab for resectable non-small-cell lung cancer (NSCLC): results from a multicenter study (IFCT-1601 IONESCO)
Authors: Marie Wislez, Julien Mazieres, Armelle Lavole, Gérard Zalcman, Olivier Carre, Thomas Egenod, Raffaele Caliandro, Catherine Dubos-Arvis, Gaelle Jeannin, Olivier Molinier, Marie-Ange Massiani, Alexandra Langlais, Franck Morin, Francoise Le Pimpec Barthes, Laurent Brouchet, Jalal Assouad, Bernard Milleron, Diane Damotte, Martine Antoine, Virginie Westeel
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background The IONESCO (IFCT-1601) trial assessed the feasibility of neoadjuvant durvalumab, for early-stage resectable non-small-cell lung cancer (NSCLC). Methods In a multicenter, single-arm, phase II trial, patients with IB (≥4 cm)-IIIA, non-N2, resectable NSCLC received three doses of durvalumab (750 mg every 2 weeks) and underwent surgery between 2 and 14 days after the last infusion. The primary endpoint was the complete surgical resection rate. Secondary endpoints included tumor response rate, major histopathological response (MPR: ≤10% remaining viable tumor cells), disease-free survival (DFS), overall survival (OS), durvalumab-related safety, and 90-day postoperative mortality ( NCT03030131 ). Results Forty-six patients were eligible (median age 60.9 years); 67% were male, 98% were smokers, and 41% had squamous cell carcinoma. Regarding tumor response, 9% had a partial response, 78% had stable disease, and 13% had progressive disease. Among the operated patients (n=43), 41 achieved complete resection (89%, 95% CI 80.1% to 98.1%)), and eight achieved MPR (19%). The 12-month median OS and DFS rates were 89% (95% CI 75.8% to 95.3%) and 78% (95% CI 63.4% to 87.7%), respectively (n=46). The median follow-up was 28.4 months (12.8–41.1). All patients in whom MPR was achieved were disease-free at 12 months compared to only 11% of those with &gt;10% residual tumor cells (p=0.04). No durvalumab-related serious or grade 3–5 events were reported. The unexpected 90-day postoperative mortality of four patients led to premature study termination. None of these four deaths was considered secondary to direct durvalumab-related toxicity. Conclusions Neoadjuvant durvalumab given as monotherapy was associated with an 89% complete resection rate and an MPR of 19%. Despite an unexpectedly high rate of postoperative deaths, which prevented us from completing the trial, we were able to show a significant association between MPR and DFS.
ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update
Authors: Sofia Ramiro, Elena Nikiphorou, Alexandre Sepriano, Augusta Ortolan, Casper Webers, Xenofon Baraliakos, Robert B M Landewé, Filip E Van den Bosch, Boryana Boteva, Ann Bremander, Philippe Carron, Adrian Ciurea, Floris A van Gaalen, Pál Géher, Lianne Gensler, Josef Hermann, Manouk de Hooge, Marketa Husakova, Uta Kiltz, Clementina López-Medina, Pedro M Machado, Helena Marzo-Ortega, Anna Molto, Victoria Navarro-Compán, Michael J Nissen, Fernando M Pimentel-Santos, Denis Poddubnyy, Fabian Proft, Martin Rudwaleit, Mark Telkman, Sizheng Steven Zhao, Nelly Ziade, Désirée van der Heijde
Journal: Annals of the Rheumatic Diseases (2022)

To update the Assessment of SpondyloArthritis international Society (ASAS)-EULAR recommendations for the management of axial spondyloarthritis (axSpA).Following the EULAR Standardised Operating Procedures, two systematic literature reviews were conducted on non-pharmacological and pharmacological treatment of axSpA. In a task force meeting, the evidence was presented, discussed, and overarching principles and recommendations were updated, followed by voting.Five overarching principles and 15 recommendations with a focus on personalised medicine were agreed: eight remained unchanged from the previous recommendations; three with minor edits on nomenclature; two with relevant updates (#9, 12); two newly formulated (#10, 11). The first five recommendations focus on treatment target and monitoring, non-pharmacological management and non-steroidal anti-inflammatory drugs (NSAIDs) as first-choice pharmacological treatment. Recommendations 6-8 deal with analgesics and discourage long-term glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs (DMARDs) for pure axial involvement. Recommendation 9 describes the indication of biological DMARDs (bDMARDs, that is, tumour necrosis factor inhibitors (TNFi), interleukin-17 inhibitors (IL-17i)) and targeted synthetic DMARDs (tsDMARDs, ie, Janus kinase inhibitors) for patients who have Ankylosing Spondylitis Disease Activity Score ≥2.1 and failed ≥2 NSAIDs and also have either elevated C reactive protein, MRI inflammation of sacroiliac joints or radiographic sacroiliitis. Current practice is to start a TNFi or IL-17i. Recommendation 10 addresses extramusculoskeletal manifestations with TNF monoclonal antibodies preferred for recurrent uveitis or inflammatory bowel disease, and IL-17i for significant psoriasis. Treatment failure should prompt re-evaluation of the diagnosis and consideration of the presence of comorbidities (#11). If active axSpA is confirmed, switching to another b/tsDMARD is recommended (#12). Tapering, rather than immediate discontinuation of a bDMARD, can be considered in patients in sustained remission (#13). The last recommendations (#14, 15) deal with surgery and spinal fractures.The 2022 ASAS-EULAR recommendations provide up-to-date guidance on the management of patients with axSpA.
XBP1 Activation Reduces Severity of Polycystic Kidney Disease due to a Nontruncating Polycystin-1 Mutation in Mice
Authors: Matteus Krappitz, Rishi Bhardwaj, Ke Dong, Tobias Staudner, Duygu Elif Yilmaz, Carlotta Pioppini, Parisa Westergerling, David Ruemmele, Till Hollmann, Thuy Anh Nguyen, Yiqiang Cai, Anna-Rachel Gallagher, Stefan Somlo, Sorin Fedeles
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement XBP1 activation in neonatal and adult doxycycline-inducible murine models of ADPKD due to a hypomorphic polycystin-1 missense mutation orthologous to human PC1R2220W delays cyst formation. Activating XBP1s, a pro-chaperone inducer of the endoplasmic reticulum stress response, can improve steady-state expression, ciliary trafficking, and cleavage of the mutant protein, providing initial in vivo proof of concept that modulating levels of poorly functioning hypomorphic PC1 alleles can slow progression of kidney cyst formation in ADPKD. Background Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in Pkd1 and Pkd2. They encode the polytopic integral membrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively, which are expressed on primary cilia. Formation of kidney cysts in ADPKD starts when a somatic second hit mechanism inactivates the wild-type Pkd allele. Approximately one quarter of families with ADPDK due to Pkd1 have germline nonsynonymous amino acid substitution (missense) mutations. A subset of these mutations is hypomorphic, retaining some residual PC1 function. Previous studies have shown that the highly conserved Ire1 α -XBP1 pathway of the unfolded protein response can modulate levels of functional PC1 in the presence of mutations in genes required for post-translational maturation of integral membrane proteins. We examine how activity of the endoplasmic reticulum chaperone-inducing transcription factor XBP1 affects ADPKD in a murine model with missense Pkd1 . Methods We engineered a Pkd1 REJ domain missense murine model, Pkd1R2216W , on the basis of the orthologous human hypomorphic allele Pkd1R2220W , and examined the effects of transgenic activation of XBP1 on ADPKD progression. Results Expression of active XBP1 in cultured cells bearing PC1 R2216W mutations increased levels and ciliary trafficking of PC1 R2216W . Mice homozygous for Pkd1R2216W or heterozygous for Pkd1R2216W in trans with a conditional Pkd1fl allele exhibit severe ADPKD following inactivation in neonates or adults. Transgenic expression of spliced XBP1 in tubule segments destined to form cysts reduced cell proliferation and improved Pkd progression, according to structural and functional parameters. Conclusions Modulating ER chaperone function through XBP1 activity improved Pkd in a murine model of PC1, suggesting therapeutic targeting of hypomorphic mutations.
Systematic Review of Advanced AI Methods for Improving Healthcare Data Quality in Post COVID-19 Era
Authors: Monica Isgut, Logan Gloster, Katherine Choi, Janani Venugopalan, May D. Wang
Journal: IEEE Reviews in Biomedical Engineering (2022)

At the beginning of the COVID-19 pandemic, there was significant hype about the potential impact of artificial intelligence (AI) tools in combatting COVID-19 on diagnosis, prognosis, or surveillance. However, AI tools have not yet been widely successful. One of the key reason is the COVID-19 pandemic has demanded faster real-time development of AI-driven clinical and health support tools, including rapid data collection, algorithm development, validation, and deployment. However, there was not enough time for proper data quality control. Learning from the hard lessons in COVID-19, we summarize the important health data quality challenges during COVID-19 pandemic such as lack of data standardization, missing data, tabulation errors, and noise and artifact. Then we conduct a systematic investigation of computational methods that address these issues, including emerging novel advanced AI data quality control methods that achieve better data quality outcomes and, in some cases, simplify or automate the data cleaning process. We hope this article can assist healthcare community to improve health data quality going forward with novel AI development.
Shedding Patterns of Genital Herpes Simplex Virus Infections
Authors: Richard J. Whitley, Edward W. Hook
Journal: JAMA (2022)

Christine Johnston, MD; Amalia Magaret, PhD; Hyunju Son, MSc; Michael Stern, ARNP; Molly Rathbun, PhD; Daniel Renner, MS; Moriah Szpara, PhD; Sarah Gunby, MD; Mariliis Ott, BS; Lichen Jing, MD, PhD; Victoria L. Campbell, BS; Meei-li Huang, PhD; Stacy Selke, MS; Keith R. Jerome, MD, PhD; David M. Koelle, MD; Anna Wald, MD
Scalp biomarkers during dupilumab treatment support Th2 pathway pathogenicity in alopecia areata
Authors: Yael Renert‐Yuval, Ana B. Pavel, Ester Del Duca, Paola Facheris, Angel D. Pagan, Swaroop Bose, Pedro J. Gómez‐Arias, Michael Angelov, Jennifer Bares, Margo Chima, Yeriel D. Estrada, Sandra Garcet, Mark G. Lebwohl, James G. Krueger, Emma Guttman‐Yassky
Journal: Allergy (2022)

The mechanisms driving alopecia areata (AA) are still unclear, hindering development of targeted therapeutics. Specific Th2 targeting with dupilumab in AA provides a unique opportunity to dissect its pathogenesis and explore the role of Th2 pathway.
Rewiring the altered tryptophan metabolism as a novel therapeutic strategy in inflammatory bowel diseases
Authors: Chloé Michaudel, Camille Danne, Allison Agus, Aurélie Magniez, Anne Aucouturier, Madeleine Spatz, Antoine Lefevre, Julien Kirchgesner, Nathalie Rolhion, Yazhou Wang, Aonghus Lavelle, Chloé Galbert, Gregory Da Costa, Maxime Poirier, Alexia Lapière, Julien Planchais, Petr Nádvorník, Peter Illes, Cyriane Oeuvray, Laura Creusot, Marie-Laure Michel, Nicolas Benech, Anne Bourrier, Isabelle Nion-Larmurier, Cecilia Landman, Mathias L Richard, Patrick Emond, Philippe Seksik, Laurent Beaugerie, Rafael Rose Arguello, David Moulin, Sridhar Mani, Zdenek Dvorák, Luis G Bermúdez-Humarán, Philippe Langella, Harry Sokol
Journal: Gut (2022)

The extent to which tryptophan (Trp) metabolism alterations explain or influence the outcome of inflammatory bowel diseases (IBDs) is still unclear. However, several Trp metabolism end-products are essential to intestinal homeostasis. Here, we investigated the role of metabolites from the kynurenine pathway.Targeted quantitative metabolomics was performed in two large human IBD cohorts (1069 patients with IBD). Dextran sodium sulphate-induced colitis experiments in mice were used to evaluate effects of identified metabolites. In vitro, ex vivo and in vivo experiments were used to decipher mechanisms involved. Effects on energy metabolism were evaluated by different methods including Single Cell mEtabolism by profiling Translation inHibition.In mice and humans, intestinal inflammation severity negatively correlates with the amount of xanthurenic (XANA) and kynurenic (KYNA) acids. Supplementation with XANA or KYNA decreases colitis severity through effects on intestinal epithelial cells and T cells, involving Aryl hydrocarbon Receptor (AhR) activation and the rewiring of cellular energy metabolism. Furthermore, direct modulation of the endogenous tryptophan metabolism, using the recombinant enzyme aminoadipate aminotransferase (AADAT), responsible for the generation of XANA and KYNA, was protective in rodent colitis models.Our study identified a new mechanism linking Trp metabolism to intestinal inflammation and IBD. Bringing back XANA and KYNA has protective effects involving AhR and the rewiring of the energy metabolism in intestinal epithelial cells and CD4+ T cells. This study paves the way for new therapeutic strategies aiming at pharmacologically correcting its alterations in IBD by manipulating the endogenous metabolic pathway with AADAT.
A novel compound EPIC-0412 reverses temozolomide resistance via inhibiting DNA repair/MGMT in glioblastoma
Authors: Jixing Zhao, Shixue Yang, Xiaoteng Cui, Qixue Wang, Eryan Yang, Fei Tong, Biao Hong, Menglin Xiao, Lei Xin, Can Xu, Yanli Tan, Chunsheng Kang
Journal: Neuro-Oncology (2022)

Temozolomide (TMZ) resistance has become an important obstacle affecting its therapeutic benefits. O6-methylguanine DNA methyltransferase (MGMT) is primarily responsible for the TMZ resistance in Glioblastoma multiforme (GBM) patients. In addition, active DNA damage repair pathways can also lead to TMZ resistance. Here, we reported a novel small-molecule inhibitor EPIC-0412 that improved the therapeutic efficacy of TMZ by inhibiting the DNA damage repair pathway and MGMT in GBM via epigenetic pathways.The small-molecule compound EPIC-0412 was obtained through high-throughput screening. RNA immunoprecipitation (RIP), chromatin isolation by RNA purification (ChIRP), and chromatin immunoprecipitation (ChIP) assays were used to verify the effect of EPIC-0412. Co-immunoprecipitation (Co-IP) was used to elucidate the interactions of transcription factors at the MGMT promoter region. Animal experiments using a mouse model were performed to verify the efficacy of EPIC-0412 in sensitizing GBM cells to TMZ.EPIC-0412 physically interrupts the binding of HOTAIR and EZH2, leading to the upregulation of CDKN1A and BBC3, causing cell cycle arrest and apoptosis in GBM cells. EPIC-0412 inhibits DNA damage response in GBM cells through the p21-E2F1 DNA damage repair axis. EPIC-0412 epigenetically silences MGMT through its interaction with the ATF3-p-p65-HADC1 axis at the MGMT promoter region. The application of EPIC-0412 restored the TMZ sensitivity in GBM in vivo experiments.This study discovered a small-molecule inhibitor EPIC-0412, which enhanced the chemotherapeutic effect of TMZ by acting on the p21-E2F1 DNA damage repair axis and ATF3-p-p65-MGMT axis, providing evidence for combining epigenetic drugs to increase the sensitization toward TMZ in GBM patients.
Efficacy and safety of biological DMARDs: a systematic literature review informing the 2022 update of the ASAS-EULAR recommendations for the management of axial spondyloarthritis
Authors: Casper Webers, Augusta Ortolan, Alexandre Sepriano, Louise Falzon, Xenofon Baraliakos, Robert B M Landewé, Sofia Ramiro, Désirée van der Heijde, Elena Nikiphorou
Journal: Annals of the Rheumatic Diseases (2022)

To update the evidence on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) in patients with axial spondyloarthritis (axSpA) to inform the 2022 update of the Assessment of SpondyloArthritis international Society/European Alliance of Associations for Rheumatology (ASAS-EULAR) recommendations for the management of axSpA.Systematic literature review (2016-2021) on efficacy and safety of bDMARDs in axSpA (radiographic axSpA (r-axSpA)/non-radiographic axSpA (nr-axSpA)). Eligible study designs included randomised controlled trials (RCTs), strategy trials and observational studies (the latter only for safety and extra-musculoskeletal manifestations). All relevant efficacy/safety outcomes were included.In total, 148 publications were included. Efficacy of golimumab and certolizumab was confirmed. Tumour necrosis factor inhibitor (TNFi) biosimilar-originator equivalence was demonstrated. RCT (n=15) data on efficacy of interleukin-17 inhibitors (IL-17i) demonstrated clinically relevant effects (risk ratio vs placebo to achieve ASAS40 response 1.3-15.3 (r-axSpA, n=9), 1.4-2.1 (nr-axSpA, n=2)). Efficacy of secukinumab/ixekizumab was demonstrated in TNFi-naïve and TNFi-inadequate responders. IL-23 and IL-12/23 inhibitors (risankizumab/ustekinumab) failed to show relevant benefits. Tapering of TNFi by spacing was non-inferior to standard-dose treatment. The first axSpA treat-to-target trial did not meet its primary endpoint, but showed improvements in secondary outcomes. No new risks were identified with TNFi use in observational studies (data lacking for IL-17i). Secukinumab (n=1) and etanercept (n=2) were associated with increased risk of uveitis in observational studies compared to monoclonal TNFi.New evidence supports the efficacy and safety of TNFi (originators/biosimilars) and IL-17i in r-axSpA and nr-axSpA, while IL-23i failed to show relevant effects. Observational studies are needed to confirm long-term IL-17i safety.CRD42021257588.
Lenacapavir: First Approval
Authors: Julia Paik
Journal: Drugs (2022)

Abstract Lenacapavir (Sunlenca ® ) is a long-acting capsid inhibitor of human immunodeficiency virus type 1 (HIV-1) being developed by Gilead Sciences Inc. It is available as an oral tablet and injectable solution, with the latter being a slow-release formulation to allow bi-annual subcutaneous administration. In August 2022, lenacapavir received its first approval in the EU for use in combination with other antiretroviral(s) in adults with multi-drug resistant HIV infection, for whom it is otherwise not possible to construct a suppressive anti-viral regimen. This article summarizes the milestones in the development of lenacapavir leading to this first approval for the treatment of HIV-1 infection.
Viral Shedding 1 Year Following First-Episode Genital HSV-1 Infection
Authors: Christine Johnston, Amalia Magaret, Hyunju Son, Michael Stern, Molly Rathbun, Daniel Renner, Moriah Szpara, Sarah Gunby, Mariliis Ott, Lichen Jing, Victoria L. Campbell, Meei-li Huang, Stacy Selke, Keith R. Jerome, David M. Koelle, Anna Wald
Journal: JAMA (2022)

Herpes simplex virus type 1 (HSV-1) is the leading cause of first-episode genital herpes in many countries.To inform counseling messages regarding genital HSV-1 transmission, oral and genital viral shedding patterns among persons with first-episode genital HSV-1 infection were assessed. The trajectory of the development of HSV-specific antibody and T-cell responses was also characterized.Prospective cohort followed up for up to 2 years, with 82 participants followed up between 2013 and 2018. Participants were recruited from sexual health and primary care clinics in Seattle, Washington. Persons with laboratory-documented first-episode genital HSV-1 infection, without HIV infection or current pregnancy, were referred for enrollment.First-episode genital HSV-1 infection.Genital and oral HSV-1 shedding and lesion rates at 2 months, 11 months, and up to 2 years after initial genital HSV-1 infection. Participants self-collected oral and genital swabs for HSV polymerase chain reaction testing for 30 days at 2 and 11 months and up to 2 years after diagnosis of genital HSV-1. Blood samples were collected at serial time points to assess immune responses to HSV-1. Primary HSV-1 infection was defined as absent HSV antibody at baseline or evolving antibody profile using the University of Washington HSV Western Blot. HSV-specific T-cell responses were detected using interferon γ enzyme-linked immunospot.Among the 82 participants, the median (range) age was 26 (16-64) years, 54 (65.9%) were women, and 42 (51.2%) had primary HSV-1 infection. At 2 months, HSV-1 was detected from the genital tract in 53 participants (64.6%) and in the mouth in 24 participants (29.3%). Genital HSV-1 shedding was detected on 275 of 2264 days (12.1%) at 2 months and declined significantly to 122 of 1719 days (7.1%) at 11 months (model-predicted rate, 6.2% [95% CI, 4.3%-8.9%] at 2 months vs 3.2% [95% CI, 1.8%-5.7%] at 11 months; relative risk, 0.52 [95% CI, 0.29-0.93]). Genital lesions were rare, reported on 65 of 2497 days (2.6%) at 2 months and 72 of 1872 days (3.8%) at 11 months. Oral HSV-1 shedding was detected on 88 of 2247 days (3.9%) at 2 months. Persons with primary HSV-1 infection had a higher risk of genital shedding compared with those with nonprimary infection (model-predicted rate, 7.9% [95% CI, 5.4%-11.7%] vs 2.9% [95% CI, 1.7%-5.0%]; relative risk, 2.75 [95% CI, 1.40-5.44]). Polyfunctional HSV-specific CD4+ and CD8+ T-cell responses were maintained during the follow-up period.Genital HSV-1 shedding was frequent after first-episode genital HSV-1, particularly among those with primary infection, and declined rapidly during the first year after infection.
Medicare’s National Coverage Determination for Aducanumab — A One-Off or a Pragmatic Path Forward?
Authors: Sanket S. Dhruva, Reshma Ramachandran, Joseph S. Ross
Journal: New England Journal of Medicine (2022)

As it did with aducanumab, CMS could use the coverage with evidence development program to address residual uncertainty regarding benefits and harms for an increasing number of FDA-regulated products.
Medical Malpractice Law — Doctrine and Dynamics
Authors: David M. Studdert, Mark A. Hall
Journal: New England Journal of Medicine (2022)

Interview with Dr. David Studdert on the U.S. malpractice system and its effects on medical decision making. (10:06)Download Establishing a malpractice claim in the United States requires proving a defendant breached a duty of care and injury resulted. How does the process work, and why have paid claims dropped by 75% in the past 20 years?
Clonal hematopoiesis is associated with hematological toxicity during lenalidomide-based therapy for MCL
Authors: Simon Husby, Cecilie Bæch-Laursen, Christian W. Eskelund, Francesco Favero, Jakob Schmidt Jespersen, Martin Hutchings, Lone Bredo Pedersen, Carsten U. Niemann, Joachim Weischenfeldt, Riikka Räty, Thomas Stauffer Larsen, Arne Kolstad, Mats Jerkeman, Kirsten Grønbæk
Journal: Leukemia (2022)